The goal of this project is to understand the selection and regulation of autoreactive B lymphocytes in Type 1A diabetes mellitus (T1DM). In the long term this information will be used to identify new targets for the diagnosis and treatment of the disorder. Although autoantibodies to insulin, GAD and other islet antigens are recognized as early indicators of loss of immunological tolerance, most studies focus on the role of T lymphocytes in the disease. Several recent studies indicate that B lymphocytes play a critical role in NOD mice, a highly relevant animal model of IDDM. Further, data indicate that B lymphocytes are uniquely able to present some key beta cell antigens, and their antigen presenting function includes the ability to govern T cell differentiation. To better understand the role of B lymphocytes in IDDM, NOD mice were produced that express immunoglobulin transgenes (Tg) from anti-insulin mab125. NOD mice engineered to harbor only the heavy chain (HC) Tg from mab125 (VH 125Tg) develop diabetes at a significantly faster rate than non-Tg controls. In contrast, NOD mice expressing an otherwise identical transgene (VH281) that differs in only two amino acids that are required for insulin binding are protected from developing diabetes. These observations indicate that HC-Tg mice provide a unique means to understand divergent outcomes for T1DM that are governed by the B cell repertoire. The mechanisms that connect B cell actions to T cell effector functions in IDDM will be examined in the following specific aims: 1) To identify the mechanisms that govern disease progression in NOD mice harboring immunoglobulin transgenes that differ only in their potential for insulin binding. 2) To identify the mechanisms that provide protection from diabetes in NOD mice that harbor the VH281 heavy chain transgene. 3) To identify the shifts in structure and function of insulin binding B cells that coincide with progressive beta cell damage in VH125Tg mice. 4) To characterize the antigen presenting functions of B cells whose receptors govern different outcomes for diabetes.